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The Immunological System and Neoplasia
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
The basic structure and the genomic map of retroviruses are depicted in Figure 12.1. Purified viruses contain a limited number of viral proteins. Two glycoproteins are expressed on the cell surface and are important for the attachment of the virus to the cells: a transmembrane protein or spike protein to which the second glycoprotein or “knob” is attached. These proteins are identified as glycoprotein (gp) 15 and gp 70, respectively in feline leukemia virus (FeLV), the number indica ting the molecular mass in kilodaltons. In addition, the virion contains the reverse transcriptase and four structural proteins: p27 (capsid protein), p15 (matrix protein), p10 (nucieocapsid protein), and p12 (inner coat protein). After virus enters the cells, the RNA is reverse transcribed into DNA, which is incorporated into the cellular genome. The incorporated DNA will persist in these cells. This group of retroviruses does not transform cells in vitro and tumors develop only after a prolonged incubation time in hosts. Some retroviruses, however, transform cells easily in vitro, and tumors develop rapidly in vivo. These acutely transforming viruses have captured a proto-oncogene (see below) from the cellular genome replacing part of the viral genome or adding it after the env gene. The captured proto-oncogene has become a viral oncogene or v-onc. The long terminal repeat or LTR (see Figure 12.1) is a strong promoter that can overexpress the v-onc gene leading to the development of tumor cells.
Genetic Manipulation of Human Marrow: Gene Transfer Using Retroviruses
Published in Adrian P. Gee, BONE MARROW PROCESSING and PURGING, 2020
Philip Hughes, R. Keith Humphries
The production and use of recombinant retroviruses for gene transfer is outlined in Figure 1. Transcriptional control elements called long terminal repeats (LTRs) are found at either end of the provirus and contain the sequences necessary for efficient transcription of the retroviral genes. These include the promoter/enhancer sequences, CAP site and polyadenylation signal. Close to the LTR is a packaging sequence which is necessary for efficient assembly of the retroviral genome into the new virus. Approximately 80% of the provirus between the LTRs contains the structural genes, which can be deleted without influencing the transcriptional activity of the LTR or altering efficient integration. To make a retroviral vector, these structural genes are deleted and are replaced by a gene of interest. This is done in plasmids using standard genetic engineering techniques and plasmid constructions. RNA transcribed from this recombinant provirus can then form a genome for a new virus; however, this requires a source of retroviral structural proteins.
General Biological Aspects of Oncogenesis
Published in Pimentel Enrique, Oncogenes, 2020
In a few instances viruses have been used to induce differentiation of transformed cells. Highly malignant cat melanoma cells may be induced to differentiation in vitro into neuronal, nontumorigenic cells, when they are infected with the endogenous cat retrovirus RDI 14.310 Apparently, the insertion of a promoter contained in the long terminal repeat (LTR) region of the virus could alter the transcriptional control of the malignant cell, inducing its terminal differentiation.
Cytogenetic and epigenetic aberrations in peripheral lymphocytes of northwest Arkansas Marshallese
Published in International Journal of Radiation Biology, 2023
Laura E. Ewing, Rupak Pathak, Reid D. Landes, Charles M. Skinner, Regina Binz, Sean G. Young, Sheldon Riklon, Shelbie Stahr, Joseph Su, Marjan Boerma, Pearl A. McElfish, Martin Hauer-Jensen, Igor Koturbash
DNA was isolated from frozen lymphocytes using the AllPrep micro kit (Qiagen, Valencia, CA, USA) according to the manufacturer’s protocol. The REs families’ consensus sequences were obtained from the Genetic Information Research Institute (GIRI) Database: http://www.girinst.org/. Thirty two REs were identified for this study: 17 LINE-1 elements, 8 Long Terminal Repeats (LTR)/Human Endogenous Retroviruses (HERV), 3 Transposons, 3 REs associated with centromeric satellite DNA, and 1 Short Interspersed Nucleotide Element (SINE/Alu). The list of REs as well as forward and reverse primers are provided in Supplementary Table 1. The 5′-UTRs of the REs were analyzed using NEBcutter® (http://nc2.neb.com/NEBcutter2/) and the most frequent CpG sites that can are cleaved by the methylation-sensitive restriction enzymes (AciI, BstUI, HhaI, HpaII, and SmaI) were identified. Analysis of DNA methylation was performed as previously described (Prior et al. 2016). The change in methylation was calculated using the following equation:
The discovery and development of RNA-based therapies for treatment of HIV-1 infection
Published in Expert Opinion on Drug Discovery, 2023
Michelle J Chen, Anne Gatignol, Robert J. Scarborough
Hairpin and hammerhead ribozymes were developed against HIV-1 during the early 1990s [42,125,126], but their efficacy was not sufficient to reach clinical trials. Several developments have seen the emergence of effective therapeutic targets in the 5’ LTR, the coding sequences for the pol, vpr/tat and tat/rev genes [127–130]. Among those, the OZ1 ribozyme targeting the tat-vpr region reached phase II clinical trials when delivered with a murine retroviral vector [115]. Although this single ribozyme was not sufficient to demonstrate strong inhibition against HIV-1 replication, the trial showed that no adverse effects occurred during the treatment and the follow-up. Identification of more active ribozymes came from the development of HDV ribozymes against HIV-1 [131,132]. HDV ribozyme 1498 showed a particularly strong inhibition of HIV-1 replication that could be maintained for a long period due to the high stability of HDV ribozymes, which evolved in human cells [133]. Ribozymes have also been developed to target the HIV-1 entry co-receptor, CCR5 [134]. One of these has entered clinical trials in combination with a shRNA and a TAR decoy delivered with a lentiviral vector [116]. The trial showed that their expression is safe, but their long-term application is limited because of declining expression over time with a decrease to 1% after 4 weeks. Although CCR5 ribozymes could have been improved, the development of gene editing of CCR5 has supplanted their use in gene therapy [135,136].
Human endogenous retrovirus K (HERV-K) env in neuronal extracellular vesicles: a new biomarker of motor neuron disease
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2022
Yuan Li, Yong Chen, Nan Zhang, Dongsheng Fan
Human endogenous retroviruses (HERVs) are remnants of provirus genome that integrated into the human genome through infection over several million years (1,2), accounting for approximately 8% of the human genome (3). As humans evolved, most HERVs lost transcriptional activity due to deletions or stop codons in the reading frames, but some HERVs have complete open reading frames (ORFs) that can express viral protein particles or proviruses. Currently, HERV-K has been confirmed as the most active, and it can express complete functional proteins. HERVs and exogenous retroviruses, such as human immunodeficiency virus (HIV), have similar genetic structures, with long terminal repeats (LTRs) and gag, pro, pol, and env regions, which encodes envelope proteins (4). The env protein is structurally divided into surface unit (SU) and transmembrane (TM) moieties. Whether HERV-K Env protein is functional is a matter of debate, but some evidence suggests SU may serve as a receptor and participate in membrane fusion and immune regulation, TM may relate to intracellular signal transduction (5).